Patients with acute leukemia who have relapsed or are refractory to induction therapy have 5-year overall survivals of less than 20%, and are typically considered poor risk for allogeneic hematopoietic stem cell transplantation (HSCT). City of Hope helped pioneer the use of image-guided intensity-modulated radiotherapy technologies to precisely deliver targeted radiation, known as total marrow and lymphoid irradiation (TMLI). TMLI sculpts the radiation to areas of high risk and disease burden, allowing intensification of radiation dose to target structures, in this case the bone marrow and major lymph organs, while decreasing the radiation-related toxicities to off-target critical organs typically seen with TBI. e have developed a high-intensity HSCT conditioning regimen for advanced acute leukemia patients with refractory disease, that combines TMLI with cyclophosphamide (Cy) and etoposide (VP16). Our completed phase I clinical trial demonstrated that TMLI/Cy/VP16 conditioning is tolerated at TMLI doses from 1200 to 2000 cGy. This proposed phase II study of TMLI/Cy/VP16 for HSCT conditioning is innovative in its use of 2000 cGy TMLI to intensify the HSCT regimen for patients entering transplant with active disease. This regimen, if effective has the potential o give patients with refractory acute leukemia an HSCT curative option. Initial efforts at City of Hope have already led to other centers in Asia, Europe and the U.S. beginning their own pilot or phase I trials. Hypothesis: The TMLI/Cy/VP16 HSCT conditioning regimen will improve progression-free survival over historical rates for TBI-based regimens in patients with active acute leukemia, through enhanced disease control and decreased radiation-related toxicity. Specific Aim: In a phase II trial, assess the activity of TMLI combined with cyclophosphamide and etoposide as conditioning for HSCT in patients with treatment refractory acute leukemia. This protocol has the primary objective of evaluating the anti-tumor activity of a regimen combining 2000 cGy TMLI with 100 mg/kg Cy and 60 mg/kg VP16, as assessed by 2-year progression-free survival (PFS). Secondary objectives include estimating incidence (severity) of toxicities, overall survival, cumulative incidence of relapse/progression, and non-relapse mortality, and incidence (location) of extramedullary relapse. We will also assess the possible relationship between pre-HSCT disease status, radiation doses delivered to targeted/spared regions, and outcomes. Environment: Our team is ideally suited to execute the proposed studies. The City of Hope HSCT program is well established and regarded, performing over 500 transplants yearly and 12,000 since 1976. A dedicated and multi-disciplinary TMLI HSCT team is already in place, with more than 230 TMLI patients treated to date and 4 clinical trials completed. A TomoTherapy(r) machine and PET/CT scanner are committed to this project. Timeline: We will accrue 34 patients to this trial, and should have sufficient follow-up to publish late in year 3.